Human epidermal growth factor receptor (EGFR; HER1,erbB1), human epidermal growth factor r eceptor 2 (HER2; erbB2), HER3 (erbB3) and HER4 (erbB4) are members of the ErbB family of transmembrane receptor tyrosine kinases. Among them, HER2 is a validated and high-value target. Approximately 30% of breast cancers have an amplification of the HER2/neu gene or overexpression of its protein product, HER2. Also, overexpression of HER2 occurs in gastric, colorectal, NSCLC and ovarian cancers. Irbinitinib is a selective and potent HER2 inhibitor with IC50 value of 8nM, ~500-fold selective for HER2 than EGFR, thus avoiding EGFR-related side effects[1]. Irbinitinib had very good PK/ADME properties both in vitro and in vivo and showed excellent activity in numerous mouse tumor models, including breast (BT-474, MDA-MB-453), ovarian (SKOV-3) and gastric (N87) carcinoma models. Daily oral treatment with Irbinitinib for 90 days achieved tumor growth inhibition by 50% at 50mg/kg and 96% at 100mg/kg in BT-474 model. Daily oral treatment with Irbinitinib, BID, for 90 days achieved tumor growth inhibition by 39% at 50 mg/kg and by 96% at 100 mg/kg in an SKOV-3 model[2].
To determine the passive transcellular permeability and interaction with ABCB1 and ABCG2 for Tucatinib
Clin Cancer Res. 2022 Aug 2;28(15):3329-3341.
HaCaT cells
1 µM, 2.5 µM
1 hour
To assess the efficacy of tucatinib in inhibiting ErbB2 phosphorylation, results showed that tucatinib effectively inhibited ErbB2 phosphorylation, particularly at Y877 and Y1221/1222 sites.
Front Immunol. 2024 Feb 2;15:1335302.
BT474-Br
0 to 200 nM
4 days
To evaluate the effect of combined tucatinib and trastuzumab treatment on the proliferation of HER2+ breast cancer brain metastasis cells. The results showed that the combination therapy significantly inhibited tumor cell proliferation.
Proc Natl Acad Sci U S A. 2022 Jan 4;119(1):e2112491119.
AU565
0 to 200 nM
4 days
To evaluate the effect of combined tucatinib and trastuzumab treatment on the proliferation of HER2+ breast cancer brain metastasis cells. The results showed that the combination therapy significantly inhibited tumor cell proliferation.
Proc Natl Acad Sci U S A. 2022 Jan 4;119(1):e2112491119.
BT474
10 nM
72 hours
Tucatinib significantly reduced the metabolic activity of HER2-overexpressing BT474 cells and enhanced the effects of radiation therapy.
Cancer Cell Int. 2024 Aug 6;24(1):277.
ZR7530
10 nM
72 hours
Tucatinib significantly reduced the metabolic activity of HER2-overexpressing ZR7530 cells and enhanced the effects of radiation therapy.
Cancer Cell Int. 2024 Aug 6;24(1):277.
HCC1954
1 µM
72 hours
Tucatinib significantly reduced the metabolic activity of HER2-overexpressing HCC1954 cells and enhanced the effects of radiation therapy.
Cancer Cell Int. 2024 Aug 6;24(1):277.
SKBR3 cells
100 nM
To evaluate the inhibitory effect of Tucatinib on HER2+ breast cancer cells, results showed that NF1-deficient cells exhibited resistance to Tucatinib.
Nat Commun. 2021 Nov 18;12(1):6667.
HCC1954 cells
2 µM
To evaluate the inhibitory effect of Tucatinib on HER2+ breast cancer cells, results showed that NF1-deficient cells exhibited resistance to Tucatinib.
Nat Commun. 2021 Nov 18;12(1):6667.
Tucatinib 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
BT-474 xenograft model
Oral
1 mg/kg
Daily for four weeks
To evaluate the therapeutic effect of MEK inhibitor on HER2+ breast cancer, results showed that NF1-deficient tumors exhibited a partial response to MEK inhibition.
Nat Commun. 2021 Nov 18;12(1):6667.
Nude mice
LS180-HER2 cell line-derived xenograft model
Intravenous injection
10 mg/kg
Administered on day 1, 7, and 21
Trastuzumab deruxtecan significantly delayed tumor progression and prolonged survival in the LS180-HER2 cell line-derived xenograft model.
Clin Cancer Res. 2024 Apr 15;30(8):1669-1684
Nude mice
HER2+ breast cancer brain metastasis model
Oral
20 mg/kg
Once daily for 21 consecutive days
To evaluate the effect of combined tucatinib and LM008-HER2Ab neural stem cell therapy on the survival of mice with HER2+ breast cancer brain metastasis. The results showed that the combination therapy significantly prolonged the survival of mice.
Proc Natl Acad Sci U S A. 2022 Jan 4;119(1):e2112491119.
MMTV-Balb/c and FVB/N mice
HER2-positive breast cancer models
Oral
25, 50, or 100 mg/kg
Once daily for 100 days or to ethical limits
Tucatinib significantly inhibited tumor growth in both models and demonstrated dose-dependent efficacy, and combination with PD-1 or PD-L1 inhibitors significantly improved survival in mice
J Natl Cancer Inst. 2023 Jul 6;115(7):805-814
Mice
Orthotopic patient-derived xenografts of HER2+ breast cancer brain metastases
Oral
75 mg/kg
Twice daily for several weeks
To evaluate the efficacy of combined treatment with tucatinib and abemaciclib in HER2+ breast cancer brain metastasis models, the results showed that the combined treatment significantly inhibited tumor growth and prolonged mouse survival.
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